Present dietetic needs, predilections, and perceptions have led to the increased use of artificial sweeteners as a replacement for the "natural" sugars, including sucrose and fructose. Such artificial sweeteners are highly imperfect, including being under continual review for their long term physiological affects, yet their demand has grown unabated. Accompanying their growth as a commercial area with substantial economic impact has been a renewed emphasis on discovering and supplying new artificial sweeteners.
The ideal artificial sweetener would be noncaloric, noncariogenic, without detrimental physiological effects, and usable by diabetics. All these requirements would be met if a sweetener were not metabolized by humans and by flora which are found in the mouth and intestinal tract, and if the sweetener were either not absorbed by humans, or absorbed without effect on any internal organ. That is, the ideal sweetener should be excreted in the same form as when ingested. Another desirable feature is that it have bulk properties similar to sucrose so that it can be substituted for table sugar in many formulations. Recently, and perhaps belatedly, attention has turned toward the L-sugars as desirable artificial sweeteners. It has been known since at least 1946 that L-fructose is sweet (M. L. Wolfrom and A. Thompson, J. Am. Chem. Soc., 68, 791,793 (1946)), and since at least 1890 that L-fructose is nonfermentable (E. Fischer, Ber. Deutsch. Chem. Ges., 23, 370,389 (1890)), hence not metabolized by microorganisms generally metabolizing D-sugars. A reasonable, although not necessarily correct, inference is that it also is not metabolized by humans. Assuming that L-fructose is a sweet nonmetabolite it becomes obvious to use it as a noncaloric sweetener in many formulations. More recently Shallenberger and coworkers have demonstrated that many L-sugars have a sweetness comparable to their D-enantiomorphs. Nature, 221, 555 (1969). Cf. R. S. Shallenberger, "The Theory of Sweetness," in Sweeteners and Sweetness, pp 42-50, Edited by G. G. Birch and coworkers; R. S. Shallenberger and T. E. Acree in "The Handbook of Sensory Physiology," Vol. 4, pp 241-5, Edited by L. M. Beider (Springer Verlag, 1971).
Exploitation of the favorable properties of L-sugars is hindered by their relative unavailability. L-Fructose, for example, is not found to any significant extent in nature. This unavailability has spurred recent efforts in developing commercially feasible methods for preparing L-sugars in amounts necessary for their use as a staple of commerce. U.S. Pat. Nos. 4,371,616 and 4,421,568 describe a method of producing L-sugars, including L-idose and L-glucose, from the readily available D-glucose. Although the preparation of a number of L-sugars is described in U.S. Pat. No. 4,262,032 the focus seems to be on typical laboratory methods wholly unsuited for economical industrial production, in contrast to the process herein. U.S. Pat. No. 4,440,855 presents a flow scheme for the preparation of a mixture of L-glucose and L-mannose. The subject matter of U.S. Pat. No. 4,207,413 is L-sucrose, the enantiomer of ordinary table sugar, which can be hydrolyzed to afford L-fructose and L-glucose.
Where L-glucose is sought it is usually found in admixture with L-mannose. A process affording such a mixture of L-glucose and L-mannose is described in U.S. Pat. No. 4,581,447. Although separation of L-glucose from L-mannose can be effected in various ways the presence of mannose in the separation feedstock increases the cost of the purified L-glucose, with its cost increasing with increasing mannose content in the feedstock. Unfortunately, a mixture of L-glucose and L-mannose generally is produced under kinetic control with the L-mannose in preponderance, which imposes heavy cost penalties upon the production of relatively pure L-glucose. Since glucose is thermodynamically favored relative to mannose (Hayes et al., J. Amer. Chem. Soc., 104, 6764 (1982)) it follows that if the separation feedstock would represent an equilibrium mixture of L-glucose and L-mannose, substantial and quite significant reductions in cost would accrue.
One could obtain an equilibrium mixture for separation either by producing the glucose-mannose mixture under equilibrium control, or by equilibrating a kinetically controlled product mixture. For various reasons the latter appeared the more promising route, which led to our evaluation of different equilibrating means. Given the intended use for L-glucose the requirements of minimum by-products and color body formation and minimum costs were mandatory.
The requisites for epimerizing L-mannose to L-glucose in a mixture containing both led to our focus on soluble molybdate as the equilibrating means. Bilik in Czechoslovak Certificate of Authorship 149,463 has demonstrated that molybdic acid epimerizes aqueous solutions of L-mannose to, supposedly, a 3:1 mixture of L-glucose:L-mannose. Hayes et al., op. cit., have elucidated some mechanistic aspects of this epimerization. In fact, molybdate readily epimerizes pure mannose. It was with great consternation to discover that under similar conditions molybdate failed to effect epimerization in a reaction product mixture of L-mannose and L-glucose- Further investigation into this unexpected phenomenon led to the cause of this failure, and continued investigation afforded a means of circumventing such problems.